Table Of ContentAdnanetal.JournalofMedicalCaseReports2013,7:26
JOURNAL OF MEDICAL
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CASE REPORTS
CASE REPORT Open Access
Simultaneous occurrence of medullary and
papillary thyroid microcarcinomas: a case series
and review of the literature
Zaina Adnan1*, Eldad Arad1, James Dana2, Yaakov Shendler3 and Elzbieta Baron1
Abstract
Introduction: Papillary thyroid microcarcinoma has been demonstrated to present in association with medullary
thyroid carcinoma, however, medullary thyroidcarcinoma and papillary thyroid carcinoma represent rare entities. In
recent years this rarity has been increasingly observed. The pathogenesis is still controversial. Genetic analysis ofRET
proto-oncogenes incases of simultaneous papillary thyroid carcinoma and medullary thyroid carcinoma has so far
provided conflictingresults; although it seems that germlinemutationsplay a potential role inthe development of
both histologicaltypes.
Case presentations: Thispaper describes four rarecases ofsimultaneous medullary thyroidcarcinoma and
papillary thyroid microcarcinoma withuniquefeatures:
Case one was a 43-year-oldJewish woman, born in Israel, daughter of a Latvian immigrantmother and a father
born in Israel. Case twowas a 44-year-old Arab woman born in Israel. Case threewas a 45-year-oldJewish woman,
born in Israel, daughter ofMoroccan immigrant parents and is unique for the presence of lymph nodemetastatic
medullary thyroid carcinoma, and one lymphnode with metastatic papillary carcinoma found inthe same side.
Case four was a 77-year-oldJewish woman, born in Iraq. These cases are unique in their composition ofthyroid
carcinoma, consisting ofhistologic features of medullary thyroid carcinoma, papillary thyroidmicrocarcinoma, and
follicular thyroid adenoma.The four cases represent different ethnicity groups that live in north Israel, and case four
is notable for theadvanced age ofthepatient (77 years).
Conclusion: These four cases add more data supporting the coincidental coexistence of papillary thyroid
microcarcinoma and medullary thyroid carcinoma; our results may suggest thatthe simultaneous occurrence of
medullary thyroid carcinoma and papillary thyroid microcarcinoma is generally a simple reflection ofthis
coincidence. Endocrinologists and pathologists should be aware of this entity. The pathologist can play a pivotal
rolein identifying papillary thyroidmicrocarcinoma in concurrent existence with medullary thyroid carcinoma.
Keywords: Calcitonin RET proto-oncogene, Medullary thyroid carcinoma, Papillarythyroidcarcinoma, Papillary
thyroid microcarcinoma
Introduction from the parafollicular C-cell which originates in the
Papillary thyroid carcinoma (PTC), the most common ultimobranchial body of the neural crest. MTC synthe-
type of thyroid carcinoma (75% to 80%), originates sizes and secretes calcitonin and other neuroendocrine
from follicular cells of the endoderm. PTC synthesizes peptides[1].
thyroglobulin, organic iodine (I), and thyroid hor- The cell origin and histopathological features of PTC
mones. Medullary thyroid carcinoma (MTC) repre- and MTC have been considered to differ. In the English
sentsonly5%to8%ofthyroidcarcinomas.Itisderived literature, 71 cases of concurrent PTC and MTC have
been reported. Cases with PTC and MTC presenting
*Correspondence:[email protected] together in the same primary tumor, termed a ‘mixed
1TheInstituteofEndocrinology,ZvulunMedicalCenter-ClalitMedical medullary and follicular thyroid carcinoma’ (MMFTC),
Services,AkkoStr.192,KiryatBialik,Israel
Fulllistofauthorinformationisavailableattheendofthearticle represent the simultaneous occurrence of rare and
©2013Adnanetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Adnanetal.JournalofMedicalCaseReports2013,7:26 Page2of5
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distinctly different entities. Lamberg et al. first reported
MTC with PTC in 1981 [2]. In 2004, Biscolla et al. A
reported high rates of concurrent PTC (13.8%, 27 out of
196) in patients with MTC and, recently, in 2010, Kim
et al. identified simultaneous PTC (19%, 10 out of 53) in
patients with MTC [3,4]. These reported cases displayed
well separated MTC and PTC, and there was a high
tendency of papillary thyroid microcarcinoma (PTMC)
with atumor sizelessthan orequaltoone cm.
Our goal is to describe four additional cases of this
rare entity, review the literature, and emphasize the
important roles of the endocrinologist and pathologist in
identifyingnewpatientswiththis rareassociation.
Cases presentations
Case1
A 43-year-old Jewish woman, born in Israel, the
daughter of a Latvian immigrant mother and a father
born in Israel, was referred to our medical center for B
multinodular goiter evaluation; there was no apparent
family history of endocrine disorders or any previous
external radiation therapy. Fine needle aspiration
(FNA) disclosed a proliferative lesion suspicious for
neoplasia. In 2005, the patient underwent a two-stage
total thyroidectomy and right modified neck dissection
for MTC. On macroscopic examination, the specimen
revealed two separate tumors: the first one, a well-
demarcated two cm maximal diameter lesion, and a
second lesion measuring 1.2cm. The distance between
the two masses was 0.9cm. Microscopy from the right
lobe and isthmus disclosed medullary carcinoma meas-
uring two cm in diameter. The tumor was composed of
nests of oval cells with diffusely stippled nuclei staining
positiveforcalcitoninandnegativeforthyroglobulin.
C
A 1.2cm in diameter follicular adenoma, with a
microfollicular pattern, was partially circumscribed by a
thin capsule. The tumor cells, with rounded nuclei,
distinct nucleoli, and clumped chromatin, stained posi-
tive for thyroglobulin. Calcitonin staining showed a few
small positive cell groups, but was otherwise negative.
The non-neoplastic thyroid tissue revealed lymphocytic
infiltration and occasional colloid nodules. The left
thyroid lobe histology disclosed a tiny focus, two mm
in size, consistent with micropapillary carcinoma
(Figure 1). No lymph node metastasis was found. The
patient’s presurgical calcitonin level (2170ng/L, normal
value <13ng/L), carcinoembryonic antigen (CEA) level
(51mg/L, normal reference range value less than
five mg/L), and thyroid-stimulating hormone were
Figure1(A)Papillarythyroidcarcinoma,hematoxylinand
within the normal range. The patient was treated surgi-
eosinstaining,magnification×400;(B)Positivethyroglobulin
cally followed by I-131 100 mCi. immunostainingforpapillarythyroidcarcinoma,magnification
One year postsurgery, the patient’s calcitonin levels ×400;(C)Negativethyroglobulinimmunostaininginmedullary
were less than five ng/L, and her thyroglobulin levels thyroidcarcinoma,magnification×200.
were no longer measurable. Point mutation for RET
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proto-oncogene was tested by deoxyribonucleic acid level, before her second operation, was 800ng/L, and
(DNA) analysis of the peripheral leukocytes and found 24-hour metanephrines and catecholamines were within
to be negative (RET exon 8, 10, 11, 13–16 and RETgene normalrange.
mutationexon5weretested). After her second operation, the patient underwent
neck US, indium-111 somatostatin scan (Octreoscan™),
Case2 positron emission tomography-CTand whole body scan
A 44-year-old Arab woman, born in Israel, was referred with I-131,which ruledout further malignancy.
to our department for evaluation of a thyroid nodule. Her calcitonin level remains persistently slightly high
The presurgical FNA, taken from the right lobe, sug- (10.4ng/L), and her thyroglobulin level and thyroglobu-
gested follicular neoplasia. In October 2007, the patient lin antibodies were undetectable under levothyroxine
underwent right thyroidectomy and isthmectomy. therapy.
Analysis of the intraoperative frozen section disclosed Detection for point mutation of the RET proto-
the presence of carcinoma, with high suspicion of MTC, oncogen germline was negative by DNA polymerase
and subsequent total thyroidectomy was performed. chain reaction (PCR) analysis of peripheral leukocytes
The histology of the right lobe disclosed medullary DNA (RET exon 8, 10, 11 13–16, and RET gene muta-
carcinoma one cm in diameter, staining positively for tion exon5were tested).
calcitonin, chromogranin, synaptophysin, and partially
for CEA. Congo red histochemical stain and polarized Case4
microscopy disclosed no evidence of amyloid. A tiny A 77-year-old Jewish woman, born in Iraq, presented to
microscopic focus less than 0.1cm in diameter, consistent our clinic for management of a right thyroid nodule
with PTMC, was documented. The left lobe histology discovered by neck CT that had been ordered due to
revealed a 1.3cm nodule compatible with follicular aden- cervical spine pain. She was under medical treatment for
oma. Following surgery, the patient underwent right osteoporosis, for eight years, with alendronate. The
modifiedneckdissection.Nolymphnodemetastaseswere patient denied any family history of endocrine disorder,
detected and I-131 100 mCi therapy was performed for thyroid carcinoma, or radiation exposure. Her thyroid
remnant ablation. Point mutation of the RET proto- US disclosed a solid thyroid nodule in the right lobe,
oncogene was found to be negative by DNA analysis of 1.63cminsize, with peripheralhypervascularization.US-
the peripheral leukocytes (RET exon 8, 10, 11, 13–16 and guided FNA diagnosed follicular neoplasia. The results
RETgenemutationexon5weretested). of her preoperative thyroid function tests and calcium
level were normal. In February 2011, the patient under-
Case3 went surgery consisting of right side thyroidectomy and
A 45-year-old Jewish woman, born in Israel, the isthmectomy. The histology results showed a hyperplas-
daughter of Moroccan immigrant parents was referred tic nodule with a small focus of 0.4cm of papillary
to our clinic for a multinodular goiter. Ultrasound carcinoma within a 1.7cm follicular adenoma. A 0.2cm
examination of her neck showed a multinodular goiter focus of MTC was found a distance of 0.3cm from the
with averysuspicioushypoechoic,notwelldemarcated, inked thyroid surface. It stained positive for calcitonin,
rightlobelesionmeasuring 1.2cm.Theleft lobeshowed CEA and pankeratin. One month postoperatively, her
two nodules, 0.9cm and 0.6cm in size. The patient calcitonin level was less than 0.2ng/L, CEA level 1.2
underwent ultrasonography (US)-guided FNA. The 189mg/L (normal reference range value less than
resultswerehighlysuspiciousforfollicularneoplasia.In five mg/L), and her thyroglobulin, due to partial thyroi-
August 2007, a total thyroidectomy was performed, dectomy, remained 39mcg/L. Her thyroid function tests,
which disclosed a 1.2cm diameter right medullary calcium level, and 24-hour metanephrines and catecho-
thyroid and multiple foci of papillary carcinoma with a lamineswere allwithin the normallevels.
maximaldiameterof0.4cm,bothintherightlobe. Detection for point mutation of the RET proto-
One month later, a chest computed tomography (CT) oncogen germline was negative by DNA PCR analysis of
disclosed three small lung nodules up to 6mm in peripheral leukocytes (RET exon 8, 10, 11 13, 14, 15, 16,
diameter. andRETgenemutation exon5were tested).
Two months later, a right side modified neck dissection ThefourcasesaresummarizedinTable1.
and central compartment dissection were performed.
Histology revealed that 11 out of 30 lymph nodes had Discussion
metastatic medullary carcinoma, levels IIA, IIB, III–IV, The simultaneous, discreet, existence of PTC and MTC,
and one lymph node out of 10 had metastatic papillary separated by normal tissue, is increasingly being identi-
carcinoma, level V–VI. External beam radiotherapy and fied. This entity differs from MMFTC, which is defined
I-131 remnant ablation were performed. Her calcitonin as a primary tumor showing morphological features of
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Table1Clinicalcharacteristicsoffourpatientswith Other possible explanations for the simultaneous
concurrentmedullarythyroidcarcinomaandpapillary coexistence may be linked to the presence of RETproto-
thyroidmicrocarcinoma oncogene mutation in both papillary and medullary
No. Age Sex Pathology Size Laterality Lymphno thyroid cells [8]. Sporadic MTC is associated with about
(years) (cm) metastasis 30% to 50% of cases with mutations in the RET proto-
1. 43 F MTC 2.0 R none oncogene [9]. Point mutations and rearrangements of
thetyrosinekinasereceptorsRET(ret/PTC)andNTRK1
FTA 1.2 R
have been characterized as specific for PTC, and have
PTMC 0.2 L none
been documented in about 20% to 40% of cases [8-10].
2. 44 F MTC 1.0 R none
A somaticpoint mutation ofthe BRAFgene hasrecently
PTMC 0.1 R none
been identified as the most common genetic event in
FTA 1.3 L
PTC[11-13].
3. 45 F MTC 1.2 R present The exact explanation for these rare simultaneous
PTMC 0.4 R present tumors is somewhat unclear.Thereare different theor-
4. 77 F MTC 0.3 R none ies regarding synchronous solid organ malignancies.
PTMC 0.4 R none One possible explanation is the ‘common stem cell
theory’ as proposed by Ljungberg et al. [14]. These
FTA 1.7 R
authors postulated that there might be a common
FTAfollicularthyroidadenoma;Lleftlobe;MTCmedullarythyroidcarcinoma;
PTMCpapillarythyroidmicrocarcinoma;Rrightlobe. progenitor cell, possibly in the ultimobranchial body,
which undergoes divergent differentiation giving rise
MTC together with immunoreactivity of calcitonin, and tobothparafollicularandfollicularcelllines.
the morphological features of follicular carcinoma with This theory is supported by the presence of the same
reactivitytothyroglobulin [5]. receptors and immunochemical markers in both tumors
Reviewing the English literature, about 77% (55 cases despite theirdifferentembryologic origins[14].
out of 71) of the papillary component presented as Another potential theory is a common tumorigenic
PTMC, including the cases presented in this manuscript stimulus such as radiation exposure that promotes the
(Table 2). PTMC is defined as PTC with a tumor size malignant transformation of both endodermal and
less than or equal to one cm at the greatest diameter. neural crest-derived cell lines [15]. Genetic analysis of
PTMC accounts for up to 30% of all PTC in some surgi- RET oncogene in cases of simultaneous PTC and MTC
cal series, and up to 35% of the general population dis- hassofarprovidedconflictingresults[16,17].
played PTMC in autopsy series [6,7]. Similar to our The more appealing hypothesis, reported in most
results, Kim et al. identified PTMC in all their study studies, refers to a potential role of RET germline
patients. mutations in the development of both histological
Based on our observations, we may suggest that most types.
cases of concurrent MTC and PTMC are a coincidence.
One possible explanation isthatthe sections wereexam-
Conclusions
ined in too thin a slice to disclose these pathological
Intheabsenceofacommonbackgroundofthefourcases
abnormalities. The cases presented here were examined
presented here (the patients had different ethnicities and
by the same pathologist at one location. Therefore, care-
livedindifferentsmallcitiesinthenorthernpartofIsrael)
ful pathological examination represents a key point in
and despite the limited number of patients, we may
disclosingthiscombinationofpathology.
conclude that the majority of concurrent MTC and PTC,
especiallyPTMCcases, mightsimplybecoincidental,and
Table2Literaturereviewofthecaseswithconcurrent
relatedtoacarefulpathologicalexamination.
medullarythyroidandpapillarythyroidcarcinoma
Our findings are supported by previously published
No.of F:M No.ofmicro: CervicalLN
cases macroPTC Metastasis* data. Endocrinologists and pathologists should keep in
mindthepossible coexistence oftheseentities.
Case 30 19:11 20:10 16
reports
Biscollaet 27 18:9 21:6 11
Consent
al.
Written informed consents were obtained from the
Kimetal. 10 9:1 10:0 4
patients for publication of these case reports and any
Ourcases 4 4:0 4:0 1
accompanying images. Copies of the written consents
Ffemale;Mmale;MTCmedullarythyroidcarcinoma;PTCpapillarythyroid
are available for review by the Editor-in-Chief of
carcinoma;LNlymphnode.
*MTC,PTCandPTCwithMTC. thisjournal.
Adnanetal.JournalofMedicalCaseReports2013,7:26 Page5of5
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Abbreviations 12. CohenY,XingM,MamboE,GuoZ,WuG,TrinkB,BellerU,WestraWH,
CEA:Carcinoembryonicantigen;CT:Computedtomography;FNA:Fine LadensonPW,SidranskyD:BRAFmutationinpapillarythyroidcarcinoma.
needleaspiration;I:Iodine;MMFTC:Mixedmedullaryandfollicularthyroid JNatlCancerInst2003,95:625–627.
carcinoma;MTC:Medullarythyroidcarcinoma;PCR:Polymerasechain 13. XuX,QuirosRM,GattusoP,AinKB,PrinzRA:HighprevalenceofBRAF
reaction;PTC:Papillarythyroidcarcinoma;PTMC:Papillarythyroid genemutationinpapillarythyroidcarcinomasandthyroidtumorcell
microcarcinoma;US:Ultrasonography. lines.CancerRes2003,63:4561–4567.
14. LjungbergO,EricssonUB,BondesonL,ThorellJ:Acompoundfollicular-
parafollicularcellcarcinomaofthethyroid:anewtumorentity?
Competinginterests
Cancer1983,52:1053–1061.
Theauthorsdeclarethattheyhavenocompetinginterests.
15. TriggsSM,WilliamsED:Experimentalcarcinogenesisinthethyroid
follicularandCcells.Acomparisonoftheeffectofvariationindietary
Authors’contributions calciumandofradiation.ActaEndocrinol(Copenh)1977,85:84–92.
ZAwasthephysician,draftedandeditedthemanuscriptandobtainedthe 16. FugazzolaL,MannavolaD,CirelloV,VannucchiG,MuzzaM,VicentiniL,
patients’informedconsents.EAsearchedforpreviousrelevantcasesand Beck-PeccozP:BRAFmutationsinanItaliancohortofthyroidcancers.
reviewedtheeditedmanuscript.JDparticipatedinpreparingthemanuscript ClinEndocrinol2004,61:239–243.
andcheckedspelling.YSperformedthepathologicalmaterial.BEwasthe 17. PapiG,CorradoS,PomponiMG,CarapezziC,CesinaroA,LiVolsiVA:
attendingphysicianintheout-patientclinicandtheendocrinologistwho Concurrentlymphnodemetastasesofmedullaryandpapillarythyroid
attendedthepatientsinhospitalandtookcareofthemduringtheentire carcinomainacasewithREToncogenegermlinemutation.EndocrPathol
period.Allauthorsreadandapprovedthefinalmanuscript. 2003,14:269–276.
Acknowledgements doi:10.1186/1752-1947-7-26
TheauthorswishtothankDrBaronforherhelpfulsuggestionsandremarks. Citethisarticleas:Adnanetal.:Simultaneousoccurrenceofmedullary
andpapillarythyroidmicrocarcinomas:acaseseriesandreviewofthe
Authordetails literature.JournalofMedicalCaseReports20137:26.
1TheInstituteofEndocrinology,ZvulunMedicalCenter-ClalitMedical
Services,AkkoStr.192,KiryatBialik,Israel.2TheCatholicMedicalCenter,
Manchester,NH03102,USA.3TheInstituteofPathologyCarmelMedical
Center,Haifa,Israel.
Received:23August2012Accepted:28November2012
Published:21January2013
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